1887

Abstract

The first extensively drug resistant (XDR) Neisseria gonorrhoeae strain with high resistance to the extended-spectrum cephalosporin ceftriaxone was identified in 2009 in Japan, but no other strain with this antimicrobial-resistance profile has been reported since. However, surveillance to date has been based on phenotypic methods and sequence typing, not genome sequencing. Therefore, little is known about the local population structure at the genomic level, and how resistance determinants and lineages are distributed and evolve. We analysed the whole-genome sequence data and the antimicrobial-susceptibility testing results of 204 strains sampled in a region where the first XDR ceftriaxone-resistant N. gonorrhoeae was isolated, complemented with 67 additional genomes from other time frames and locations within Japan. Strains resistant to ceftriaxone were not found, but we discovered a sequence type (ST)7363 sub-lineage susceptible to ceftriaxone and cefixime in which the mosaic penA allele responsible for reduced susceptibility had reverted to a susceptible allele by recombination. Approximately 85 % of isolates showed resistance to fluoroquinolones (ciprofloxacin) explained by linked amino acid substitutions at positions 91 and 95 of GyrA with 99 % sensitivity and 100 % specificity. Approximately 10 % showed resistance to macrolides (azithromycin), for which genetic determinants are less clear. Furthermore, we revealed different evolutionary paths of the two major lineages: single acquisition of penA X in the ST7363-associated lineage, followed by multiple independent acquisitions of the penA X and XXXIV in the ST1901-associated lineage. Our study provides a detailed picture of the distribution of resistance determinants and disentangles the evolution of the two major lineages spreading worldwide.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Loading

Article metrics loading...

/content/journal/mgen/10.1099/mgen.0.000205
2018-07-31
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/mgen/4/8/mgen000205.html?itemId=/content/journal/mgen/10.1099/mgen.0.000205&mimeType=html&fmt=ahah

References

  1. Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 2015; 13:42–51 [View Article][PubMed]
    [Google Scholar]
  2. Sugden R, Kelly R, Davies S. Combatting antimicrobial resistance globally. Nat Microbiol 2016; 1:16187 [View Article][PubMed]
    [Google Scholar]
  3. CDC Antibiotic Resistance Threats in the United States. Atlanta, GA: Centers for Disease Control and Prevention; 2013 www.cdc.gov/drugresistance/threat-report-2013/index.html
    [Google Scholar]
  4. Newman L, Rowley J, vander Hoorn S, Wijesooriya NS, Unemo M et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One 2015; 10:e0143304 [View Article][PubMed]
    [Google Scholar]
  5. WHO Global Incidence and Prevalence of Selected Curable Sexually Transmitted Infections Geneva: World Health Organization; 2008 www.who.int/reproductivehealth/publications/rtis/2008_STI_estimates.pdf
    [Google Scholar]
  6. WHO Global Action Plan to Control the Spread and Impact of Antimicrobial Resistance in Neisseria gonorrhoeae Geneva: World Health Organization; 2012 http://whqlibdoc.who.int/publications/2012/9789241503501_eng.pdf
    [Google Scholar]
  7. Tapsall JW, Ndowa F, Lewis DA, Unemo M. Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae. Expert Rev Anti Infect Ther 2009; 7:821–834 [View Article][PubMed]
    [Google Scholar]
  8. Goire N, Lahra MM, Chen M, Donovan B, Fairley CK et al. Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance. Nat Rev Microbiol 2014; 12:223–229 [View Article][PubMed]
    [Google Scholar]
  9. Ohnishi M, Golparian D, Shimuta K, Saika T, Hoshina S et al. Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother 2011; 55:3538–3545 [View Article][PubMed]
    [Google Scholar]
  10. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A et al. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012; 56:1273–1280 [View Article][PubMed]
    [Google Scholar]
  11. Bignell C, Unemo M, Radcliffe K, Jensen JS, Babayan K et al. 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS 2013; 24:85–92 [View Article]
    [Google Scholar]
  12. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1–137[PubMed]
    [Google Scholar]
  13. de Silva D, Peters J, Cole K, Cole MJ, Cresswell F et al. Whole-genome sequencing to determine transmission of Neisseria gonorrhoeae: an observational study. Lancet Infect Dis 2016; 16:1295–1303 [View Article][PubMed]
    [Google Scholar]
  14. Ronholm J, Nasheri N, Petronella N, Pagotto F. Navigating microbiological food safety in the era of whole-genome sequencing. Clin Microbiol Rev 2016; 29:837–857 [View Article][PubMed]
    [Google Scholar]
  15. Allen VG, Melano RG. Whole-genome sequencing-new tools for gonorrhoea control. Lancet Infect Dis 2016; 16:1214–1215 [View Article][PubMed]
    [Google Scholar]
  16. Ohnishi M, Unemo M. Phylogenomics for drug-resistant Neisseria gonorrhoeae. Lancet Infect Dis 2014; 14:179–180 [View Article][PubMed]
    [Google Scholar]
  17. Grad YH, Kirkcaldy RD, Trees D, Dordel J, Harris SR et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet Infect Dis 2014; 14:220–226 [View Article][PubMed]
    [Google Scholar]
  18. Grad YH, Harris SR, Kirkcaldy RD, Green AG, Marks DS et al. Genomic epidemiology of gonococcal resistance to extended-spectrum cephalosporins, macrolides, and fluoroquinolones in the United States, 2000–2013. J Infect Dis 2016; 214:1579–1587 [View Article][PubMed]
    [Google Scholar]
  19. Shimuta K, Unemo M, Nakayama S, Morita-Ishihara T, Dorin M et al. Antimicrobial resistance and molecular typing of Neisseria gonorrhoeae isolates in Kyoto and Osaka, Japan, 2010 to 2012: intensified surveillance after identification of the first strain (H041) with high-level ceftriaxone resistance. Antimicrob Agents Chemother 2013; 57:5225–5232 [View Article][PubMed]
    [Google Scholar]
  20. Wi T, Lahra MM, Ndowa F, Bala M, Dillon JR et al. Antimicrobial resistance in Neisseria gonorrhoeae: global surveillance and a call for international collaborative action. PLoS Med 2017; 14:e1002344 [View Article][PubMed]
    [Google Scholar]
  21. Coil D, Jospin G, Darling AE. A5-miseq: an updated pipeline to assemble microbial genomes from Illumina MiSeq data. Bioinformatics 2015; 31:587–589 [View Article][PubMed]
    [Google Scholar]
  22. Unemo M, Golparian D, Sánchez-Busó L, Grad Y, Jacobsson S et al. The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization. J Antimicrob Chemother 2016; 71:3096–3108 [View Article][PubMed]
    [Google Scholar]
  23. Maiden MC, Harrison OB. Population and functional genomics of Neisseria revealed with gene-by-gene approaches. J Clin Microbiol 2016; 54:1949–1955 [View Article][PubMed]
    [Google Scholar]
  24. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics 2014; 30:2068–2069 [View Article][PubMed]
    [Google Scholar]
  25. Zhang G, Leclercq SO, Tian J, Wang C, Yahara K et al. A new subclass of intrinsic aminoglycoside nucleotidyltransferases, ANT(3")-II, is horizontally transferred among Acinetobacter spp. by homologous recombination. PLoS Genet 2017; 13:e1006602 [View Article][PubMed]
    [Google Scholar]
  26. Darling AE, Mau B, Perna NT. progressiveMauve: multiple genome alignment with gene gain, loss and rearrangement. PLoS One 2010; 5:e11147 [View Article][PubMed]
    [Google Scholar]
  27. Grad YH, Kirkcaldy R, Trees D, Dordel J, Goldstein E et al. O03.4 Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the United States. Sex Transm Infect 2013; 89:A31.2–A31 [View Article]
    [Google Scholar]
  28. Didelot X, Pang B, Zhou Z, McCann A, Ni P et al. The role of China in the global spread of the current cholera pandemic. PLoS Genet 2015; 11:e1005072 [View Article][PubMed]
    [Google Scholar]
  29. Kurtz S, Phillippy A, Delcher AL, Smoot M, Shumway M et al. Versatile and open software for comparing large genomes. Genome Biol 2004; 5:R12 [View Article][PubMed]
    [Google Scholar]
  30. Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W et al. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol 2010; 59:307–321 [View Article][PubMed]
    [Google Scholar]
  31. Didelot X, Wilson DJ. ClonalFrameML: efficient inference of recombination in whole bacterial genomes. PLoS Comput Biol 2015; 11:e1004041 [View Article][PubMed]
    [Google Scholar]
  32. Méric G, Yahara K, Mageiros L, Pascoe B, Maiden MC et al. A reference pan-genome approach to comparative bacterial genomics: identification of novel epidemiological markers in pathogenic Campylobacter. PLoS One 2014; 9:e92798 [View Article][PubMed]
    [Google Scholar]
  33. Shimuta K, Watanabe Y, Nakayama S, Morita-Ishihara T, Kuroki T et al. Emergence and evolution of internationally disseminated cephalosporin-resistant Neisseria gonorrhoeae clones from 1995 to 2005 in Japan. BMC Infect Dis 2015; 15:378 [View Article][PubMed]
    [Google Scholar]
  34. Nakayama S, Shimuta K, Furubayashi K, Kawahata T, Unemo M et al. New ceftriaxone- and multidrug-resistant Neisseria gonorrhoeae strain with a novel mosaic penA gene isolated in Japan. Antimicrob Agents Chemother 2016; 60:4339–4341 [View Article][PubMed]
    [Google Scholar]
  35. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol 2013; 30:2725–2729 [View Article][PubMed]
    [Google Scholar]
  36. Harrison OB, Clemence M, Dillard JP, Tang CM, Trees D et al. Genomic analyses of Neisseria gonorrhoeae reveal an association of the gonococcal genetic island with antimicrobial resistance. J Infect 2016; 73:578–587 [View Article][PubMed]
    [Google Scholar]
  37. Katoh K, Standley DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 2013; 30:772–780 [View Article][PubMed]
    [Google Scholar]
  38. Benjamini Y YH. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B 1995; 57:289–300
    [Google Scholar]
  39. Demczuk W, Martin I, Peterson S, Bharat A, van Domselaar G et al. Genomic epidemiology and molecular resistance mechanisms of azithromycin-resistant Neisseria gonorrhoeae in Canada from 1997 to 2014. J Clin Microbiol 2016; 54:1304–1313 [View Article][PubMed]
    [Google Scholar]
  40. Jacobsson S, Golparian D, Cole M, Spiteri G, Martin I et al. WGS analysis and molecular resistance mechanisms of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 2014. J Antimicrob Chemother 2016; 71:3109–3116 [View Article][PubMed]
    [Google Scholar]
  41. Hunt M, Mather AE, Sánchez-Busó L, Page AJ, Parkhill J et al. ARIBA: rapid antimicrobial resistance genotyping directly from sequencing reads. Microb Genom 2017; 3:000131 [View Article][PubMed]
    [Google Scholar]
  42. Jolley KA, Maiden MC. BIGSdb: scalable analysis of bacterial genome variation at the population level. BMC Bioinformatics 2010; 11:595 [View Article][PubMed]
    [Google Scholar]
  43. Hadfield J, Croucher NJ, Goater RJ, Abudahab K, Aanensen DM et al. Phandango: an interactive viewer for bacterial population genomics. Bioinformatics 2018; 34:292–293 [View Article][PubMed]
    [Google Scholar]
  44. Croucher NJ, Page AJ, Connor TR, Delaney AJ, Keane JA et al. Rapid phylogenetic analysis of large samples of recombinant bacterial whole genome sequences using Gubbins. Nucleic Acids Res 2015; 43:e15 [View Article][PubMed]
    [Google Scholar]
  45. Rambaut A, Lam TT, Carvalho LM, Pybus OG. Exploring the temporal structure of heterochronous sequences using TempEst (formerly Path-O-Gen). Virus Evol 2016; 2:vew007 [View Article][PubMed]
    [Google Scholar]
  46. Didelot X, Croucher NJ, Bentley SD, Harris SR, Wilson DJ. Bayesian inference of ancestral dates on bacterial phylogenetic trees. bioRxiv 2018
    [Google Scholar]
  47. Suchard MA, Lemey P, Baele G, Ayres DL, Drummond AJ et al. Bayesian phylogenetic and phylodynamic data integration using BEAST 1.10. Virus Evol 2018; 4:vey016 [View Article][PubMed]
    [Google Scholar]
  48. Baele G, Lemey P, Suchard MA. Genealogical working distributions for bayesian model testing with phylogenetic uncertainty. Syst Biol 2016; 65:250–264 [View Article][PubMed]
    [Google Scholar]
  49. Rambaut A, Drummond AJ, Xie D, Baele G, Suchard MA. Posterior summarisation in Bayesian phylogenetics using Tracer 1.7. Syst Biol
    [Google Scholar]
  50. Vos M, Didelot X. A comparison of homologous recombination rates in bacteria and archaea. ISME J 2009; 3:199–208 [View Article][PubMed]
    [Google Scholar]
  51. Ameyama S, Onodera S, Takahata M, Minami S, Maki N et al. Mosaic-like structure of penicillin-binding protein 2 gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime. Antimicrob Agents Chemother 2002; 46:3744–3749 [View Article][PubMed]
    [Google Scholar]
  52. Unemo M, del Rio C, Shafer WM. Antimicrobial resistance expressed by Neisseria gonorrhoeae: a major global public health problem in the 21st century. Microbiol Spectr 2016; 4:EI10-0009-2015
    [Google Scholar]
  53. Vincent LR, Kerr SR, Tan Y, Tomberg J, Raterman EL et al. In vivo-selected compensatory mutations restore the fitness cost of mosaic penA alleles that confer ceftriaxone resistance in Neisseria gonorrhoeae. MBio 2018; 9:e01905-17 [View Article][PubMed]
    [Google Scholar]
  54. Whittles LK, White PJ, Didelot X. Estimating the fitness cost and benefit of cefixime resistance in Neisseria gonorrhoeae to inform prescription policy: a modelling study. PLoS Med 2017; 14:e1002416 [View Article][PubMed]
    [Google Scholar]
  55. Ledda A, Price JR, Cole K, Llewelyn MJ, Kearns AM et al. Re-emergence of methicillin susceptibility in a resistant lineage of Staphylococcus aureus. J Antimicrob Chemother 2017; 72:1285–1288 [View Article][PubMed]
    [Google Scholar]
  56. Chen SC, Yin YP, Dai XQ, Unemo M, Chen XS. First nationwide study regarding ceftriaxone resistance and molecular epidemiology of Neisseria gonorrhoeae in China. J Antimicrob Chemother 2016; 71:92–99 [View Article][PubMed]
    [Google Scholar]
  57. Chen Y, Gong Y, Yang T, Song X, Li J et al. Antimicrobial resistance in Neisseria gonorrhoeae in China: a meta-analysis. BMC Infect Dis 2016; 16:108 [View Article][PubMed]
    [Google Scholar]
  58. Kunz AN, Begum AA, Wu H, D'Ambrozio JA, Robinson JM et al. Impact of fluoroquinolone resistance mutations on gonococcal fitness and in vivo selection for compensatory mutations. J Infect Dis 2012; 205:1821–1829 [View Article][PubMed]
    [Google Scholar]
  59. Vereshchagin VA, Ilina EN, Malakhova MV, Zubkov MM, Sidorenko SV et al. Fluoroquinolone-resistant Neisseria gonorrhoeae isolates from Russia: molecular mechanisms implicated. J Antimicrob Chemother 2004; 53:653–656 [View Article][PubMed]
    [Google Scholar]
  60. Kulkarni S, Bala M, Sane S, Pandey S, Bhattacharya J et al. Mutations in the gyrA and parC genes of quinolone-resistant Neisseria gonorrhoeae isolates in India. Int J Antimicrob Agents 2012; 40:549–553 [View Article][PubMed]
    [Google Scholar]
  61. Turner KM, Christensen H, Adams EJ, McAdams D, Fifer H et al. Analysis of the potential for point-of-care test to enable individualised treatment of infections caused by antimicrobial-resistant and susceptible strains of Neisseria gonorrhoeae: a modelling study. BMJ Open 2017; 7:e015447 [View Article][PubMed]
    [Google Scholar]
  62. Sadiq ST, Mazzaferri F, Unemo M. Rapid accurate point-of-care tests combining diagnostics and antimicrobial resistance prediction for Neisseria gonorrhoeae and Mycoplasma genitalium. Sex Transm Infect 2017; 93:S65–S68 [View Article][PubMed]
    [Google Scholar]
  63. Pond MJ, Hall CL, Miari VF, Cole M, Laing KG et al. Accurate detection of Neisseria gonorrhoeae ciprofloxacin susceptibility directly from genital and extragenital clinical samples: towards genotype-guided antimicrobial therapy. J Antimicrob Chemother 2016; 71:897–902 [View Article][PubMed]
    [Google Scholar]
  64. Unemo M, Nicholas RA. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol 2012; 7:1401–1422 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/mgen/10.1099/mgen.0.000205
Loading
/content/journal/mgen/10.1099/mgen.0.000205
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Supplementary File 2

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error